Plaque bacteria generate toxins that cause oral diseases, including gingivitis and periodontal disease. Gingivitis is the initial stage of such disease, wherein the gums become red and puffy; the gums bleed when subjected to minor abrasion, as with toothbrushing; and there is persistent bad breath. Continued plaque invasion leads to periodontal disease, affecting the periodontium, which is the investing and supporting tissue surrounding a tooth (i.e. the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontitis are inflammatory disorders of the gingiva and the periodontal ligament, respectively. Gingivosis and periodontosis are more severe conditions involving degenerative disorders of the tissue.
Microorganisms contribute to both the initiation and progress of periodontal disease. These microorganisms, such as streptococcus mutans, colonize the pellicle film that surrounds each tooth, forming a soft mass. The plaque at and below the gingival margin, and the hard dental calculus that results from such plaque, causes gingivitis and subsequently periodontal pockets, pathologically deepened gingival sulcus. The body's immune response within such pockets, includes the synthesis of prostaglandins (PG), important immunoregulators, related to inflammatory response and the product of two enzyme isoforms, cyclooxygenase -1 (COX- 1) and cyclooxygenase-2 (COX-2). COX-2 is induced by cytokines, mitogens and endotoxins in inflammatory cells and is responsible for the elevated production of PG and inflammation. Offenbacher et al., J. Periodont Res., 21, 101-112 (1986) and Goodson et al., Prostaglandins, 19, 81-85 (1974) showed that extremely high levels of COX-2 are present within inflamed periodontal tissue, while COX-2 was low within such tissue in remission. The COX-2 level within active periodontal pockets approximates 1 .mu.M (Offenbacher et al., J. Periodon. Res., 19, 1-13 (1984)), a level believed to induce vasodilation, bone resorption and other pro-inflammatory responses. Accordingly, an agent having both anti-bacterial and PG inhibition properties is necessary to combat the bacterial formation of plaque and the associated gingivitis; and to inhibit the activity of COX-2, to reduce PG related inflammation and bone resorption associated with periodontal disease.
Since the 1860's, when Lister used phenol as a surgical antiseptic, it has been known that nearly all derivatives of phenol have some degree of bactericidal activity, when tested in tube dilution, disc agar, diffusion or similar assays. Dewhirst, in Prostaglandins, 20, No. 2, 209-222 (1980) examined sixty-three phenolic compounds for their ability to inhibit prostaglandin cyclooxygenase, as non-steroidal anti-inflammatory agents. Dewhirst reported that the most potent inhibitors possessing a two aromatic ring structure, connected by a short bridge, wherein one ring was apolar, the other ring contained a phenolic hydroxyl, ortho to the bridge, and the bridge contained a Lewis base such that the compounds could form bidentate metal chelates.
Three phenolic substances have been shown to inhibit caries in hamsters without adverse weight loss. Stralfors, Archs. Oral, 12, 1375-1385 (1967). The three phenolic substances were quercetin (pentahydroxyflavone), caffeic acid (3,4-dihydroxycinnamic acid) and protocatechuic acid (3,4-dihydroxybenzoic acid). Other phenolic substances are well know and widely used antimicrobials, such as thymol (2-isopropyl-5-methylphenol), which is found in commercial mouthrinse formulations. U.S. Pat. No. 5,723,500 discloses noncationic antibacterial alkylated phenol compounds for use in oral compositions which are antibacterial and provide antiplaque efficacy. U.S. Pat. No. 3,928,624 disclosed aminoethylphenols containing halogen and alkyl substituents as anti-inflammatory agents. U.S. Pat. Nos. 4,244,956 and 4,563,526 disclosed substituted 2-(arylmethoxy)phenol compounds, as medicinal agents which inhibit the synthesis of prostaglandins, inhibit platelet aggregation and are useful as topical and systemic anti-inflammatory agents. U.S. Pat. Nos. 5,512,561 and 5,677,296 disclose carbamic acid derivatives of substituted bibenzoxazepine compounds as analgesic agents for the treatment of pain, and prostaglandin-E.sub.2 (COX-2) antagonists for the treatment of prostaglandin-E.sub.2 mediated diseases. EP Patent Application 0 528 468 A1 discloses the use of triclosan (2',4,4'-trichloro-2-hydroxy-diphenyl-ether) for the inhibition and/or reduction of periodontitis, wherein triclosan inhibits cyclooxygenase activity and also reduces microbial challenge.
There is a continuing need in that art for more effective antibacterial agents compatible with anionic components in oral compositions which inhibit cyclooxygenase and PG activity; to combat plaque, gingivitis, and periodontal disease.